Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Receptors, Glycine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1992

Comparison of binding at strychnine-sensitive (inhibitory glycine receptor) and strychnine-insensitive (N-methyl-D-aspartate receptor) glycine binding sites.

We compared, for a number of ligands to the two receptors, the displacement of [3H]strychnine binding to the glycine-gated chloride channel of spinal cord and brainstem synaptic membranes to the displacement of [3H]glycine binding to the NMDA receptor complex of hippocampal and cortex synaptic membranes. Glycine and beta-alanine are recognized by both receptors. In the NMDA receptor glycine antagonists, the kynurenic acids, most of the quinoxalinediones, and the (R)-enantiomer of HA-966 had little affinity at the strychnine-sensitive site. Surprisingly, the quinoxalinedione widely used as an AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor antagonist, NBQX (2,3-dihydro-6-nitro-sulfamoylbenzo[f]quinoxaline-2,3-dione) displaced [3H]strychnine binding (IC50 = 11 microM) and to a lesser extent [3H]glycine binding (IC50 = 119 microM). Of the compounds tested, only strychnine, brucine, taurine and (S)-HA-966 were more potent displacers of [3H]strychnine than of glycine binding. Generally, the two glycine recognition sites appear to have remarkably different structural requirements.

Animals↗
PubMed1994

The inhibitory neuronal glycine receptor.

Glycine is a major inhibitory neurotransmitter in the spinal cord and in the brain stem, where it acts by activating a chloride conductance. The postsynaptic glycine receptor has been purified and contains two transmembrane subunits of 48 kDa (alpha) and 58 kDa (beta), and a peripheral membrane protein of 93 kDa. cDNA sequencing of the alpha and beta subunits has revealed a common structural organization and a strong homology between these polypeptides and the nicotinic acetylcholine and GABAA receptor proteins. The glycine receptor exhibits a heterogeneity resulting from the existence of several alpha subtypes with distinct functional properties and different developmental expressions. When present in the central nervous system in situ, as well as in primary cultures of spinal cord neurons, these receptors are localized at the postsynaptic membrane adjacent to the presynaptic release sites, thus forming functional microdomains at the neuronal surface. This distribution raises the question of the formation and the maintenance of the heterogeneity of the somato-dendritic plasma membrane.

Animals↗
PubMedDate not supplied

Midget and parasol ganglion cells of the primate retina express the alpha1 subunit of the glycine receptor.

Glycine is a major inhibitory neurotransmitter in the mammalian retina and has been shown to influence the responses of ganglion cells. Midget and parasol ganglion cells serve distinct physiological roles in the primate retina and show differences in their response characteristics to light stimuli. In the present study, we addressed the question of whether the expression of glycine receptors differs in midget and parasol ganglion cells. Ganglion cells in the retinae of marmoset and macaque monkeys were injected with Neurobiotin in a live in vitro retinal whole-mount preparation. Retinal pieces were then processed with an antibody against the alpha1 subunit of the glycine receptor. Strong punctate immunoreactivity indicative of synaptic localization is present in the ON and OFF sublamina of the inner plexiform layer. Many of the immunoreactive puncta coincide with the dendrites of both midget and parasol ganglion cells. Immunoreactive puncta are present on distal and proximal dendrites of ON and OFF cells. These results suggest that ON and OFF midget and parasol cells do not differ with respect to the distribution of the alpha1 subunit of the glycine receptor.

Animals↗
PubMed2005

Accessibility to residues in transmembrane segment four of the glycine receptor.

Glycine receptors (GlyRs) are members of the ligand-gated ion channel superfamily. Each subunit has four transmembrane segments (TM1-TM4). Several studies suggest that amino acids in all four TMs face into a water-filled, alcohol and anesthetic binding cavity in the extracellular portion of the transmembrane domain. TM4 should contribute a "wall" to this cavity, but the residues involved are unknown. Here, we determined the ability of an alcohol analog, propyl methanethiosulfonate (propyl MTS), to covalently react with twelve GlyR TM4 positions (I401-I412) after mutating the original amino acids to cysteines. Reactivity of a cysteine with propyl MTS implies that the cysteine is exposed to water. W407C, I409C, Y410C, and K411C showed altered receptor function following reaction with propyl MTS in the presence or absence of glycine. The cysteine mutations alone eliminated the effects of ethanol for I409C, Y410C, and K411C, and reduced the effects of octanol for I409C and isoflurane for K411C. The ability of propyl MTS to reduce isoflurane and chloroform potentiation was examined in the reactive mutants. Potentiation by isoflurane was significantly reduced for I409C after reaction. These data demonstrate water-accessibility of specific TM4 positions in the GlyR and suggest involvement of these residues with alcohol and anesthetic action.

Amino Acid Substitution↗
PubMed2002

Dual cooperative allosteric modulation of binding to ionotropic glycine receptors.

Glycine receptors (GlyRs) were studied via [(3)H]strychnine binding to synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied for the effects of tropeines, alcohols, minaxolone, nitrendipine, Zn(2+), muscarinic and serotonin receptor ligands. It enabled us to determine the dissociation constants of the allosteric agents (K(A)) and their cooperativity factors affecting the dissociation constants of [(3)H]strychnine (alphaK(S)) and glycine (betaK(L)). Cooperativity with [(3)H]strychnine ranged from strong negative for tropeines to weak positive for nitrendipine. Displacement curves of glycine were examined in the presence of allosteric agents. Positive cooperativities with glycine were found for submicromolar concentrations of tropisetron, bemesetron, zatosetron and nitrendipine; for tubocurarine, propofol, butanol, minaxolone, cocaine and 10 microM Zn(2+). Micromolar concentrations of tropisetron and nitrendipine showed weaker cooperativities. Other allosteric agents and 1 mM Zn(2+) displayed negative cooperativity with glycine. Binding parameters K(A) and beta correlate excellently with the activities of the allosteric agents on GlyR-ionophores. Combined inhibitory effects of the allosteric agents suggest that there are different subgroups (tropeines, alcohols and dihydropyridines) binding to distinct sites on GlyRs exerting cooperativity with glycine via a common mechanism. This is the first quantitative analysis of allosteric binding interactions for GlyRs.

Allosteric Regulation↗
PubMed1994

Glycinergic synapses in the rod pathway of the rat retina: cone bipolar cells express the alpha 1 subunit of the glycine receptor.

Glycine receptors (GlyRs) and their role in retinal circuitry were analyzed immunocytochemically in the rat retina. Specific antibodies against the alpha 1 subunit of the GlyR and against the GlyR-associated protein gephyrin, respectively, were used. In the inner plexiform layer (IPL), both antibodies produced a punctate label that was shown by electron microscopy to occur at synapses. Gephyrin-like immunoreactivity (-LI) was more widely distributed, indicating that gephyrin might also occur at nonglycinergic synapses. At the ultrastructural level, gephyrin-LI was found at the cytoplasmic face of postsynaptic membranes of amacrine and ganglion cells, but was never detected in bipolar cell axons. Immunoreactivity for the alpha 1 subunit was concentrated in the cleft of conventional synapses made by amacrine cell processes onto ganglion cell dendrites and cone bipolar axons. The latter synapses differ from other glycinergic synapses since they are not labeled by the antibody against gephyrin used in this study. In order to identify the type of bipolar cell involved in these synapses, the distribution of the alpha 1 subunit was compared with that of recoverin-immunoreactive cone bipolar cells and with that of parvalbumin-immunoreactive All-amacrine cells. Double-label immunofluorescence showed that, in the outer part of the IPL, 75% of the alpha 1-immunoreactive puncta were colocalized with recoverin-positive bipolar cell axons and 71% of the alpha 1-immunoreactive puncta were colocalized with parvalbumin-positive All-amacrine processes. Hence, the alpha 1 subunit of the GlyR is present at the chemical synapses established by All-amacrine cells with OFF-cone bipolar cells and OFF-ganglion cells. These synapses play a key role in the transmission of scotopic signals through the OFF-channel of the rod pathway.

Animals↗
PubMed1997

Biology of the postsynaptic glycine receptor.

Glycine is one of the major inhibitory neurotransmitters, and upon binding to its receptor it activates chloride conductances. Receptors are accumulated immediately opposite release sites, at the postsynaptic differentiations, where they form functional microdomains. This review describes recent advances in our understanding of the structure-function relationships of the glycine receptor, a member of the ligand-gated ion channel superfamily. Following purification of the receptor complex and identification of its integral and peripheral membrane protein components, molecular cloning has revealed the existence of several subtypes of the ligand-binding subunit. This heterogeneity is responsible for the distinct pharmacological and functional properties displayed by the various receptor configurations that are differentially expressed and assembled during development. This review also focuses on the molecular aspects of glycinergic synaptogenesis, highlighting gephyrin, the peripheral component of the receptor. The role of this cytoplasmic protein in anchoring and maintaining the channel complex in postsynaptic clusters is discussed. The glycine receptor recently moved into the spotlight as a paradigm in the approach to cell biology of the formation of the postsynaptic membrane.

Animals↗
PubMed2005

Effects of GABA receptor antagonists on retinal glycine receptors and on homomeric glycine receptor alpha subunits.

Glycinergic and GABAergic inhibition are juxtaposed at one retinal synaptic layer yet likely perform different functions. These functions have usually been evaluated using receptor antagonists. In examining retinal glycine receptors, we were surprised to find that commonly used concentrations of GABA antagonists blocked significant fractions of the glycine current. In retinal amacrine and ganglion cells, the competitive GABAA receptor antagonists (bicuculline and SR95531) were also competitive GlyR antagonists. Picrotoxinin produced a noncompetitive inhibition of retinal GlyRs. [1,2,5,6-tetrahydropyridine-4-yl] methylphosphinic acid, the GABACR antagonist, did not inhibit glycine receptors. All three GABAA receptor antagonists were competitive inhibitors of homomeric alpha1 or alpha2 GlyRs expressed in human embryonic kidney cells (HEK293) cells. Interestingly, bicuculline was much more effective at alpha2 GlyRs and might be used to separate glycine receptor subtypes. Thus commonly used concentrations of GABA antagonists do not unambiguously differentiate GABA and glycine pathways. Picrotoxinin inhibition of GABAC receptors requires two amino acids in the second transmembrane region (TM2): 2' serine and 6' threonine. Although TM2 regions in GABA and glycine receptors are highly homologous, neither 2' serine nor 6' threonine is essential for picrotoxinin sensitivity in glycine receptors.

Ambystoma↗
PubMed1995

In vivo models of cerebral ischemia: effects of parenterally administered NMDA receptor glycine site antagonists.

Both in vitro and in vivo experiments have implicated extracellular glycine in the pathogenesis of ischemic brain damage. Recently, halogenated derivatives of quinoxaline-2,3-dione have been synthesized that possess bioavailability when parenterally administered and minimal psychotomimetic properties. Such compounds have allowed investigation into the efficacy of glycine receptor antagonism as a strategy for protection against cerebral ischemic insults. Rats underwent either 90 min of middle cerebral artery filament occlusion or 10 min of forebrain ischemia with recovery while receiving intraperitoneal injections of either a glycine receptor antagonist (ACEA-1021, ACEA-1031, or ACEA-1011) or vehicle (dimethyl sulfoxide). Both ACEA-1021 and ACEA-1031 reduced cerebral infarct volumes and were associated with a reduced incidence of hemiparesis resulting from MCA occlusion. ACEA-1011, administered in a smaller dose had no effect. In the forebrain ischemia model, glycine receptor antagonism had no effect on delayed neuronal necrosis in the hippocampal CA1 sector, neocortex, or caudoputamen. We conclude that pharmacologic antagonism of glycine at the strychnine-insensitive glycine receptor presents a neuroprotective profile similar to that previously observed for antagonists of glutamate at the N-methyl-D-aspartate complex with a potential for fewer side effects.

Animals↗
PubMed1994

Effects of glycine receptor antagonism on spreading depression in the rat.

Spreading depression (SD) in the rat brain is inhibited by N-methyl-D-aspartate (NMDA) receptor antagonists. Because the NMDA receptor glycine recognition site must be occupied for activation of the NMDA ionophore, we hypothesized that antagonism of the glycine receptor would also affect SD. In halothane anesthetized rats, SD was initiated by electrocortical stimulation. Both the initiation threshold and propagation rate of SD were recorded. Rats were then administered the glycine receptor antagonist ACEA-1021 (or vehicle only) or ketamine and the stimulus was repeated. Rats were then killed and terminal depolarization was observed for. Ketamine completely inhibited initiation of SD. In contrast, all rats treated with ACEA-1021 exhibited SD. While ACEA-1021 caused no difference in the stimulation threshold for SD, propagation rate was decreased in a dose-dependent fashion. Terminal depolarization occurred in all rats. Antagonism of glycine at the NMDA receptor recognition site did not inhibit initiation of SD but played a modulatory role in the mechanism of its propagation.

Animals↗
PubMed2003

Activation of presynaptic glycine receptors facilitates glycine release from presynaptic terminals synapsing onto rat spinal sacral dorsal commissural nucleus neurons.

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Here we report the novel finding that presynaptic glycine autoreceptors modulate release from terminals synapsing onto rat spinal sacral dorsal commissural nucleus (SDCN) neurons. In mechanically dissociated SDCN neurons, in which functional presynaptic nerve terminals remain adherent to the isolated neurons, exogenously applied glycine (3 microM) increased the frequency of glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs) without affecting their amplitudes or decay times. This suggests that glycine acts presynaptically to increase glycine release probability. Picrotoxin, at a concentration that had little direct effect on sIPSC frequency and amplitude (30 microM), significantly attenuated glycine-induced presynaptic sIPSC facilitation. The glycine-induced sIPSC frequency facilitation was completely abolished either in a Ca(2+)-free external solution or in the presence of 100 microM Cd2+, suggesting the involvement of extracellular Ca2+ influx into the nerve terminals. The glycine action was also completely occluded in the presence of 300 nM tetrodotoxin. In recordings from SDCN neurons in spinal cord slices, glycine (10 microM) increased evoked IPSC (eIPSC) amplitude and decreased the extent of paired-pulse facilitation. In response to brief high frequency stimulus trains the eIPSCs displayed a profound frequency-dependent facilitation that was greatly reduced by picrotoxin (30 microM). These results indicate that glycine acts at presynaptic autoreceptors, causing depolarization of the glycinergic nerve terminals, the subsequent activation of voltage-dependent Na+ and Ca2+ channels, and facilitation of glycine release. Furthermore, this presynaptic facilitation was observed under more physiological conditions, suggesting that these glycinergic autoreceptors may contribute to the integration of local inhibitory inputs to SDCN neurons.

Algorithms↗
PubMed2002

Tyrosine kinases enhance the function of glycine receptors in rat hippocampal neurons and human alpha(1)beta glycine receptors.

Glycine receptors (GlyRs) are transmitter-gated channels that mediate fast inhibitory neurotransmission in the spinal cord and brain. The GlyR beta subunit contains a putative tyrosine phosphorylation site whose functional role has not been determined. To examine if protein tyrosine kinases (PTKs) regulate the function of GlyRs, we analysed whole-cell currents activated by applications of glycine to CA1 hippocampal neurons and spinal neurons. The role of a putative site for tyrosine phosphorylation at position 413 of the beta subunit was examined using site-directed mutagenesis and expression of recombinant (alpha(1)beta(Y413F)) receptors in human embryonic kidney (HEK 293) cells. Lavendustin A, an inhibitor of PTKs, depressed glycine-evoked currents (I(Gly)) in CA1 neurons and spinal neurons by 31 % and 40 %, respectively. In contrast, the intracellular application of the exogenous tyrosine kinase, cSrc, enhanced I(Gly) in CA1 neurons by 56 %. cSrc also accelerated GlyR desensitization and increased the potency of glycine 2-fold (control EC(50) = 143 microM; cSrc EC(50) = 74 microM). Exogenous cSrc, applied intracellularly, upregulated heteromeric alpha(1)beta receptors but not homomeric alpha(1) receptors. Substitution mutation of the tyrosine to phenylalanine at position beta-413 prevented this enhancement. Furthermore, a selective inhibitor of the Src family kinases, PP2, down-regulated wild-type alpha(1)beta but not alpha(1)beta(Y413F) receptors. Together, these findings indicate that GlyR function is upregulated by PTKs and this modulation is dependent on the tyrosine-413 residue of the beta subunit.

Animals↗
PubMed1990

An endogenous modulator of N-methyl-D-aspartate receptor-coupled glycine receptors.

Extensive washing of a membrane preparation from rat brain resulted in a progressive enhancement of strychnine-insensitive [3H]glycine binding, which was due to an increase in the number of binding sites with no changes in the apparent affinity of this radioligand, precluding an explanation based solely on the elimination of endogenous glycine. Moreover, after extensive washing a population of [3H]glycine binding sites with very high affinity for L-serine was observed in addition to the sites with low affinity for L-serine present in less extensively washed tissue. The observed changes in [3H]glycine binding were attributable to the elimination of a low molecular weight, heat-stable compound which was readily detected in the wash supernatant. Extensive washing also altered [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohept-5,10-i min e maleate ([3H]MK-801) binding to N-methyl-D-aspartate (NMDA) receptor-associated channels, decreasing basal binding at equilibrium and producing slower association rates in the presence of either glycine or L-glutamate. Moreover, in well-washed membranes both glycine and glutamate enhanced [3H]MK-801 binding acting at high- and low-affinity sites. These findings suggest that the NMDA receptor complex can assume interconverting conformational states regulated by an endogenous substance(s).

Animals↗
PubMed2004

Two different modes of action of pentobarbital at glycine receptor channels.

Glycine receptor channels are pentameric ligand-gated ion channels which respond to the binding of inhibitory transmitters by opening of a chloride-selective central pore. Pentobarbital is widely used as an anticonvulsive, hypnotic and anaesthetic drug. In the present study, the interaction between pentobarbital and glycine receptor channels was studied on outside-out patches of human embryonic kidney (HEK) 293 cells expressing alpha(1)beta glycine receptor channels. Currents elicited by 0.03 mM glycine were enhanced by pentobarbital showing potentiation of alpha(1)beta glycine receptor channels. In the presence of 1 mM glycine+pentobarbital (1 and 3 mM), desensitization was faster and the peak current amplitude decreased. After the end of glycine+pentobarbital pulses, off-currents occurred suggestive for a channel block mechanism. Pentobarbital had no agonistic effects at glycine receptor channels.

Cell Line, Transformed↗
PubMed1996

Effects of inhalational general anaesthetics on native glycine receptors in rat medullary neurones and recombinant glycine receptors in Xenopus oocytes.

1. Glycine responses were studied under voltage clamp in Xenopus oocytes injected with cDNA encoding mammalian glycine receptor subunits and in rat medullary neurones. Bath application of glycine gave strychnine-sensitive currents which reversed close to the expected equilibrium potentials for chloride ions. The peak currents for the receptors expressed in oocytes fitted a Hill equation with EC50 = 215 +/- 5 microM and Hill coefficient nH = 1.70 +/- 0.05 (means +/- s.e. means). The peak currents from the receptors in medullary neurones fitted a Hill equation with EC50 = 30 +/- 1 microM and Hill coefficient nH = 1.76 +/- 0.08. The current-voltage relationship for the receptors expressed in oocytes showed strong outward rectification (with Vrev = -21 +/- 2 mV), while that for the glycine responses from the medullary neurones in symmetrical Cl- was linear (with Vrev = 3.2 +/- 0.6 mV). 2. Inhalational general anaesthetics, at concentrations close to their human minimum alveolar concentrations (MACs), potentiated responses to low concentrations of glycine. The potentiation observed with the recombinant receptors (between 60-22%) was approximately twice that found with the medullary neurones (between 40-80%). For both the recombinant receptors and the receptors in medullary neurones, the degree of potentiation increased in the order of methoxyflurane approximately sevoflurane < halothane approximately isoflurane approximately enflurane. There was no significant difference between the potentiations observed for the two optical isomers of isoflurane. 3. For both the recombinant and native receptors, isoflurane potentiated the currents in a dose-dependent manner at low concentrations of glycine, although at high glycine concentrations the anaesthetic had no significant effect on the glycine-activated responses. The major effect of isoflurane was to cause a parallel leftward shift in the glycine concentration-response curves. The glycine EC50 concentration for the recombinant receptors decreased from a control value of 215 +/- 5 microM to 84 +/- 7 microM glycine at 610 microM isoflurane, while that for the medullary neurones decreased from a control value of 30 +/- 1 microM to 18 +/- 2 microM glycine at the same concentration of isoflurane. The potentiation was independent of membrane potential. 4. Isoflurane also potentiated responses to taurine, a partial agonist at the glycine receptor. This was observed for receptors expressed in oocytes at both low and saturating concentrations of taurine. The EC50 concentration decreased from a control value of 1.6 +/- 0.2 to 0.9 +/- 0.1 mM taurine in the presence of 305 microM isoflurane, while the maximum response to taurine increased from 47 +/- 2 to 59 +/- 2% of the maximum response to glycine. 5. Glycine receptors, like other members of the fast ligand-gated receptor superfamily, are sensitive to clinically relevant concentrations of inhalational general anaesthetics. Effects at these receptors may, therefore, play some role in the maintenance of the anaesthetic state.

Administration, Inhalation↗
PubMed1992

Modulation by NMDA Receptor Antagonists of Glycine Receptor Isoform Expression in Cultured Spinal Cord Neurons.

Two developmentally regulated isoforms of the inhibitory glycine receptor harbouring different alpha subunit variants, GlyRN (neonatal) and GlyRA (adult), have previously been identified in rodent spinal cord. Primary cultures of embyronic spinal neurons, however, express predominantly GlyRN. Here, N-methyl-d-aspartate (NMDA) receptor antagonists were found to significantly increase glycine receptor levels in mouse spinal cord cultures. In the presence of 2-amino-5-phosphonovalerate or MK-801 (dizocilpine), both GlyRN and GlyRA contents were elevated, as revealed by isoform-selective immunoassays and amplification of corresponding alpha subunit transcripts by the polymerase chain reaction. This effect of NMDA receptor antagonists was restricted to a 'sensitive' period within the second week after plating. Apparently, NMDA receptor-mediated glutamate neurotoxicity prevented GlyRA accumulation under standard culture conditions. Our data indicate that neuronal maturation in cell culture depends on conditions which minimize cell death resulting from glutamate release into the culture medium.

Journal Article↗
PubMed2005

Interaction of topiramate with glycine receptor channels.

Glycine receptor channels are pentameric ligand-gated ion channels that respond to the application of inhibitory neurotransmitters by opening of a chloride-selective central pore. Topiramate (TPM) is a broad-spectrum antiepileptic drug used as add-on or monotherapy for focal seizures. In the present study the interaction of TPM with glycine receptor channels was studied on outside-out patches from HEK293 cells expressing alpha1beta glycine receptor channels. The patch clamp techniques combined with ultra fast solution exchange enabled us to investigate the kinetics of receptor channels in presence of TPM. Our study showed no agonistic or potentiating effect for TPM on glycine receptor channels. However, in presence of 1 mM glycine + 1 mM TPM, the desensitization got faster and the peak current amplitude decreased. After the end of glycine + TPM pulses, off-currents occurred, suggestive for a specific channel block mechanism.

Cell Line↗